Metabolic mutations reduce antibiotic susceptibility of E. coli by pathway-specific bottlenecks
Abstract Metabolic variation across pathogenic bacterial strains can impact their susceptibility to antibiotics and promote the evolution of antimicrobial resistance (AMR). However, little is known about how metabolic mutations influence metabolism and which pathways contribute to antibiotic suscept...
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Springer Nature
2025-01-01
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| Series: | Molecular Systems Biology |
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| Online Access: | https://doi.org/10.1038/s44320-024-00084-z |
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| author | Paul Lubrano Fabian Smollich Thorben Schramm Elisabeth Lorenz Alejandra Alvarado Seraina Carmen Eigenmann Amelie Stadelmann Sevvalli Thavapalan Nils Waffenschmidt Timo Glatter Nadine Hoffmann Jennifer Müller Silke Peter Knut Drescher Hannes Link |
| author_facet | Paul Lubrano Fabian Smollich Thorben Schramm Elisabeth Lorenz Alejandra Alvarado Seraina Carmen Eigenmann Amelie Stadelmann Sevvalli Thavapalan Nils Waffenschmidt Timo Glatter Nadine Hoffmann Jennifer Müller Silke Peter Knut Drescher Hannes Link |
| author_sort | Paul Lubrano |
| collection | DOAJ |
| description | Abstract Metabolic variation across pathogenic bacterial strains can impact their susceptibility to antibiotics and promote the evolution of antimicrobial resistance (AMR). However, little is known about how metabolic mutations influence metabolism and which pathways contribute to antibiotic susceptibility. Here, we measured the antibiotic susceptibility of 15,120 Escherichia coli mutants, each with a single amino acid change in one of 346 essential proteins. Across all mutants, we observed modest increases of the minimal inhibitory concentration (twofold to tenfold) without any cases of major resistance. Most mutants that showed reduced susceptibility to either of the two tested antibiotics carried mutations in metabolic genes. The effect of metabolic mutations on antibiotic susceptibility was antibiotic- and pathway-specific: mutations that reduced susceptibility against the β-lactam antibiotic carbenicillin converged on purine nucleotide biosynthesis, those against the aminoglycoside gentamicin converged on the respiratory chain. In addition, metabolic mutations conferred tolerance to carbenicillin by reducing growth rates. These results, along with evidence that metabolic bottlenecks are common among clinical E. coli isolates, highlight the contribution of metabolic mutations for AMR. |
| format | Article |
| id | doaj-art-45329759f9064b0e8296aa47bf2e87c6 |
| institution | OA Journals |
| issn | 1744-4292 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-45329759f9064b0e8296aa47bf2e87c62025-08-20T01:57:40ZengSpringer NatureMolecular Systems Biology1744-42922025-01-0121327429310.1038/s44320-024-00084-zMetabolic mutations reduce antibiotic susceptibility of E. coli by pathway-specific bottlenecksPaul Lubrano0Fabian Smollich1Thorben Schramm2Elisabeth Lorenz3Alejandra Alvarado4Seraina Carmen Eigenmann5Amelie Stadelmann6Sevvalli Thavapalan7Nils Waffenschmidt8Timo Glatter9Nadine Hoffmann10Jennifer Müller11Silke Peter12Knut Drescher13Hannes Link14Interfaculty Institute of Microbiology and Infection Medicine, University of TübingenInterfaculty Institute of Microbiology and Infection Medicine, University of TübingenInterfaculty Institute of Microbiology and Infection Medicine, University of TübingenInterfaculty Institute of Microbiology and Infection Medicine, University of TübingenInterfaculty Institute of Microbiology and Infection Medicine, University of TübingenBiozentrum, University of BaselInterfaculty Institute of Microbiology and Infection Medicine, University of TübingenInterfaculty Institute of Microbiology and Infection Medicine, University of TübingenInterfaculty Institute of Microbiology and Infection Medicine, University of TübingenMax Planck Institute for Terrestrial MicrobiologyCluster of Excellence “Controlling Microbes to Fight Infections”, University of TübingenInstitute of Medical Microbiology and Hygiene, University of TübingenCluster of Excellence “Controlling Microbes to Fight Infections”, University of TübingenBiozentrum, University of BaselInterfaculty Institute of Microbiology and Infection Medicine, University of TübingenAbstract Metabolic variation across pathogenic bacterial strains can impact their susceptibility to antibiotics and promote the evolution of antimicrobial resistance (AMR). However, little is known about how metabolic mutations influence metabolism and which pathways contribute to antibiotic susceptibility. Here, we measured the antibiotic susceptibility of 15,120 Escherichia coli mutants, each with a single amino acid change in one of 346 essential proteins. Across all mutants, we observed modest increases of the minimal inhibitory concentration (twofold to tenfold) without any cases of major resistance. Most mutants that showed reduced susceptibility to either of the two tested antibiotics carried mutations in metabolic genes. The effect of metabolic mutations on antibiotic susceptibility was antibiotic- and pathway-specific: mutations that reduced susceptibility against the β-lactam antibiotic carbenicillin converged on purine nucleotide biosynthesis, those against the aminoglycoside gentamicin converged on the respiratory chain. In addition, metabolic mutations conferred tolerance to carbenicillin by reducing growth rates. These results, along with evidence that metabolic bottlenecks are common among clinical E. coli isolates, highlight the contribution of metabolic mutations for AMR.https://doi.org/10.1038/s44320-024-00084-zMetabolismAntibiotic ResistanceMutationsEscherichia coliCRISPR |
| spellingShingle | Paul Lubrano Fabian Smollich Thorben Schramm Elisabeth Lorenz Alejandra Alvarado Seraina Carmen Eigenmann Amelie Stadelmann Sevvalli Thavapalan Nils Waffenschmidt Timo Glatter Nadine Hoffmann Jennifer Müller Silke Peter Knut Drescher Hannes Link Metabolic mutations reduce antibiotic susceptibility of E. coli by pathway-specific bottlenecks Molecular Systems Biology Metabolism Antibiotic Resistance Mutations Escherichia coli CRISPR |
| title | Metabolic mutations reduce antibiotic susceptibility of E. coli by pathway-specific bottlenecks |
| title_full | Metabolic mutations reduce antibiotic susceptibility of E. coli by pathway-specific bottlenecks |
| title_fullStr | Metabolic mutations reduce antibiotic susceptibility of E. coli by pathway-specific bottlenecks |
| title_full_unstemmed | Metabolic mutations reduce antibiotic susceptibility of E. coli by pathway-specific bottlenecks |
| title_short | Metabolic mutations reduce antibiotic susceptibility of E. coli by pathway-specific bottlenecks |
| title_sort | metabolic mutations reduce antibiotic susceptibility of e coli by pathway specific bottlenecks |
| topic | Metabolism Antibiotic Resistance Mutations Escherichia coli CRISPR |
| url | https://doi.org/10.1038/s44320-024-00084-z |
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